Rheumatoid arthritis (RA) is an autoimmune disease and is characterized by chronic inflammation and progressive destruction of joint tissue. Li et al., Current Medical Research & Opinion 29(1): 85-92 (2013). The presentation of the disease and its course over time are highly variable within and between individuals. The symptoms of rheumatoid arthritis may vary from joint complaints such as pain, stiffness, swelling and functional impairment to complaints such as fatigue and loss of general health.
The majority of patients also experience progressive deterioration of cartilage and bone in the affected joints, which may eventually lead to permanent disability. The long-term prognosis of rheumatoid arthritis is poor, with approximately 50% of patients experiencing significant functional disability within 10 years from the time of diagnosis. Keystone, Rheumatology, 44 (Suppl. 2): ii8-ii12 (2005). Life expectancy is reduced by an average of 3-10 years in rheumatoid arthritis patients. Alamanosa et al., Autoimmun. Rev., 4(3): 130-136 (2005). There is also an increase in cardiovascular disease and malignancy associated with poorly controlled rheumatoid arthritis. Kaplan, Rheum. Dis. Clin. North Am., 36(2): 405-426 (2010); Llorca et al., Semin. Arthritis Rheum., 37(1): 31-38 (2007). See also Charles-Schoeman, Curr. Rheum. Rep., 14(5): 455-462 (2012); Smolen et al., Arthritis Res. & Therapy, 11: 204 (2009); Gabriel, Ann. Rheum. Dis., 67(Suppl 3): iii30-iii34 (2008); Gabriel, Am. J. Med., 121(10 Suppl 1): S9-14 (2008); Sokka et al., Clin. Exp. Rheumatol., 26(5 Suppl 51): S35-61 (2008); Naz et al., 21(5): 871-883 (2007).
Clinical management of rheumatoid arthritis requires accurate assessment of disease activity and appropriate therapeutic intervention to maintain or reduce disease. Physicians rely on a variety of indices of rheumatoid arthritis disease activity to assist in management of the disease and to guide treatment decisions to improve patient outcomes Li et al., Current Medical Research & Opinion 29(1): 85-92 (2013). Current treatment guidelines recommend regular assessment of disease activity. Id.
Swollen and tender joints counts are the historical standard that are used to assess and monitor patients. Id. Joint counts alone, however, are tedious, time-consuming, poorly reproducible and dependent on the skill and interpretation of the examiner. In an attempt to provide an overall clinical picture that integrates the heterogeneous manifestations of rheumatoid arthritis, additional indices have been developed that combine multiple measures into composite scores reflecting disease activity. Id. Some composite indices may include indirect markers of inflammation, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), in addition to joint counts. Although these indices are informative, routine clinical practice requires a quantitative measure of disease activity that is rapid, reproducible and easily performed.
The two commonly utilized laboratory indices for inflammation, ESR and CRP, are inconsistently elevated in rheumatoid arthritis. Pincus et al., Rheum. Dis. Clinic North Am., 35(4): 687-697 (November 2009). Some rheumatologists have observed that ESR and CRP level could be used guide to treatment changes, with the goal of normalization of these markers, to preserve the patient's function and prevent additional joint damage. Ten Cate et al., Arthritis Res. Ther. 15(1): R4 (2013); Young et al., Rheumatol. Rehab. 19: 14-19 (1980); Amos et al., BMJ 1: 195-197 (1977). Two other commonly available laboratory tests that are used as indices for rheumatoid arthritis disease activity are hemoglobin count and platelet count.
Other indices for rheumatoid arthritis disease activity include multiple continuous assessment indices, such as Disease Score Activity (DAS), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). At present, 63 assessment tools have been described. Anderson et al., Arthritis Care & Res. 64(5): 640-647 (2012). These tools, however, have variable accuracy and precision. Wolfe et al., Arthritis & Rheumatism 52(12): 3873-3879 (2005).
The traditional treatment of rheumatoid arthritis follows a regimented pattern, based on historical clinical trials. In recent years, the treatment philosophy has shifted to a “treat to target” approach, which reflects the awareness of the importance of biochemically neutralizing or suppressing the inflammatory processes to prevent joint damage and disability. In the last decade, there have been studies on individual biomarkers in small populations of patients with rheumatoid arthritis (e.g., measuring proteins or chemicals that contribute to inflammation) that measure the impact of treatment on individual biomarkers. Several biomarkers have also been used as an index for rheumatoid arthritis disease activity. However, the use of these biomarkers to measure rheumatoid disease activity was not applicable in a clinical setting until VECTRA® DA test by Crescendo Bioscience, Inc. became commercially available in 2010.
The VECTRA® DA test has made it possible to commercially use biomarkers to assess rheumatoid disease activity in each patient. The VECTRA® DA test measures various biomarkers that are known to play a role in rheumatoid arthritis, such as cytokines, receptors, adhesion molecules, growth factors, matrix metalloproteinases, skeletal-related proteins, hormones, and acute-phase proteins, and provides quantitative scores that correspond to disease activity. Eastman et al., J. Pharma. & Biomedical Analysis 70: 414-424 (2012).
The current “treat to target” philosophy (attempting to treat to reduce the inflammation) is blind. The practicing clinician often arbitrarily picks and changes treatments to achieve the desired goal or follows prescribed regimens that do not take into account the unique biochemical and pathophysiological characteristics of an individual patient. For example, the American College of Rheumatology has developed guidelines for the treatment of rheumatoid and juvenile chronic arthritis based on the outcomes of clinical trials. Singh et al., Arthritis Care & Research 64(4): 625-639 (2012); Beukelman et al., Arthritis Care & Research 63(4): 465-482. None of the guidelines utilize the unique biochemical physiology (disturbance) of each patient to select a treatment, and remissions have been difficult to achieve. See Zhang et al., Arthritis Res. & Therapy, 14: R156 (2012); Felson et al., Arthritis & Rheumatism, 63(3): 573-586 (2011); Ma et al., The J. of Rheum., 37(7): 1444-1453 (2010).
Additionally, with an increasingly higher number of new drugs in development, it will be progressively more difficult to select initial and subsequent treatments without an objective insight into the unique biochemical and pathophysiological characteristics of each patient. At present, one cannot predict which patient is likely to respond to a particular treatment, thus leading to a considerable trial and error, usually at considerable risk, expense, and discomfort of the patient.
It has been previously speculated that targeted therapies against newly identified biomarkers would lead to improved outcomes. Vilcek et al., Trends Pharm. Sci. 25(4): 201-209 (2004); Canella et al., Drugs 66(10): 1319-1337 (2006); Feely et al., Expert Opin. Pharmacother. 10(13): 2095-2106 (2009); Dale et al., Best Prac. Res. Clin. Rhematol. 24(4): 443-455 (2010); Allart et al., Curr. Opin. Rheu. 23(3): 421-244 (2011); Smolen et al., Nat. Rev. Drug Discov 2(6): 473-488 (2003). But, many of the targets, direct or indirect, were not commercially available until the VECTRA® DA test became available in the market.
Accordingly, there is an unmet need for a method for an objective selection of a treatment method for rheumatoid arthritis that is personalized for each patient and is based on individual patient's biochemical and pathophysiological characteristics. There is a need for more effective means for determining which patients will respond to which treatment and for incorporating such determinations into more effective treatment regimens for rheumatoid arthritis patients. Gibofsky et al., Ann. Rheum. Dis., 69(6): 941-942 (2010); Kavanaugh, Rheumatology, 5: 423-424 (2009).
The entire contents of all references cited herein are hereby incorporated by reference.